Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele

被引：90

作者：

Tin, Adrienne ^{[2
]}

Woodward, Owen M. ^{[3
]}

Kao, Wen Hong Linda ^{[2
]}

Liu, Ching-Ti ^{[4
]}

Lu, Xiaoning ^{[4
]}

Nalls, Michael A.

Shriner, Daniel ^{[5
,6
]}

Semmo, Mariam

Akylbekova, Ermeg L. ^{[7
]}

Wyatt, Sharon B. ^{[8
,9
]}

Hwang, Shih-Jen ^{[10
]}

Yang, Qiong ^{[11
]}

Zonderman, Alan B. ^{[12
]}

Adeyemo, Adebowale A. ^{[5
]}

Palmer, Cameron ^{[19
,20
,21
,22
,23
]}

Meng, Yan ^{[23
]}

Reilly, Muredach ^{[13
,14
]}

Shlipak, Michael G. ^{[15
]}

Siscovick, David ^{[16
,17
]}

Evans, Michele K. ^{[18
]}

Rotimi, Charles N.

Flessner, Michael F. ^{[24
]}

Koettgen, Michael ^{[6
]}

Cupples, L. Adrienne ^{[4
,10
]}

Fox, Caroline S. ^{[10
,25
,26
]}

Koettgen, Anna ^{[1
,2
]}

机构：

[1] Freiburg Univ Hosp, Dept Med 4, Div Renal, D-79110 Freiburg, Germany

[2] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Dept Physiol, Sch Med, Baltimore, MD 21205 USA

[4] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA

[5] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[6] Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA

[7] Jackson State Univ, Jackson, MS 39213 USA

[8] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA

[9] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA

[10] NHLBI Framingham Heart Study, Framingham, MA 01702 USA

[11] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[12] NIA, Lab Personal & Cognit, Gerontol Res Ctr, Baltimore, MD 21224 USA

[13] Univ Penn, Med Ctr, Cardiovasc Inst, Philadelphia, PA 19104 USA

[14] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94143 USA

[15] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[16] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA

[17] Univ Washington, Dept Med, Seattle, WA 98101 USA

[18] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA

[19] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[20] Childrens Hosp, Div Genet, Boston, MA 02115 USA

[21] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[22] Childrens Hosp, Program Genom, Boston, MA 02115 USA

[23] Broad Inst Harvard & MIT, Metab Dis Initiat, Cambridge, MA USA

[24] NIDDK, KUH, NIH, Bethesda, MD 20892 USA

[25] Brigham & Womens Hosp, Dept Endocrinol, Boston, MA 02115 USA

[26] Harvard Univ, Sch Med, Boston, MA USA

来源：

HUMAN MOLECULAR GENETICS | 2011年 / 20卷 / 20期

基金：

美国国家卫生研究院;

关键词：

URIC-ACID; CARDIOVASCULAR-DISEASE; GENETIC-LOCI; DESIGN; TRANSPORTER; GLUCOSE; SLC2A9; HEART; RECRUITMENT; INSIGHTS;

D O I：

10.1093/hmg/ddr307

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using C-14-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P < 5.0 x 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P = 1.0 x 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P = 3.8 x 10(-32)) and SLC22A12 (P = 2.1 x 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P = 2.7 x 10(-16)). C-14-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

引用

页码：4056 / 4068

页数：13

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